Haematologic or haematopoietic malignancies are cancers of the blood or bone marrow, including leukaemia and lymphoma. Leukaemia is characterized by the uncontrolled accumulation of blood cells, which is categorized into four types: acute lymphocytic leukaemia (ALL), acute myelogenous leukaemia (AML), chronic lymphocytic leukaemia (CLL), and chronic myelogenous leukaemia (CML).
Acute myeloid leukaemia (AML), also referred to as non-lymphoid, myeloblastic, granulocytic or myelocytic leukaemia, affects various white blood cells including granulocytes and monocytes. Acute leukaemia is a rapidly progressing disease that results in the accumulation of immature, functionless cells in the marrow and blood; the marrow often stops producing enough normal red cells, white cells and platelets and leukaemic cells spread to the liver, spleen, lymph nodes, central nervous system, kidneys and gonads. Consequently, an AML patient can develop one or more symptoms of AML such as, for example, anemia, fatigue, flu-like symptoms, bone pain, loss of appetite, weight loss, bruising easily, bleeding, and susceptibility to infection.
More than one quarter of a million adults throughout the world are diagnosed annually with acute myeloid leukaemia (AML). Despite considerable progress during the past 3 decades in the therapy of AML, two-thirds of young adults and 90% of older adults still die of their disease.
The experience from patients with haematological malignancies, and especially patients with AML, suggests that systemic plasma/serum cytokine profiles can be useful, both as a diagnostic tool and for prognostication of patients. However, cytokines/chemokines are released by a wide range of cells and are involved in a wide range of biological processes; the altered levels may therefore mainly reflect the strength and nature of the biological processes, and the optimal clinical use of chemokine/cytokine analyses may therefore require combination with organ-specific biomarkers. Chemokine levels are also altered by clinical procedures, therapeutic interventions and the general status of the patients (Reikvam H. et al., Toxins (Basel). Feb. 2013; 5(2): 336-362). Thus, novel diagnostic and prognostic methods are necessary to establish an optimal assessment and management for haematological malignancies.
Current treatments for AML may involve chemotherapy, radiotherapy, immunotherapy, blood transfusions, and bone marrow transplants. The mainstay of initial treatment, cytosine arabinoside (ara-C) combined with an anthracycline, was developed nearly 40 years ago and remains the worldwide standard of care, or alternatively a combination of from three to eight medications such as, for example, cytarabine, daunorubicin, idarubicin, thioguanine, mitoxantrone, etoposide, and methotrexate. While current chemotherapy can result in complete remissions, the long term disease-free survival rate for leukaemias, in particular AML, is low.
Alternative treatment approaches are directed to developing less toxic and more efficacious therapies. A variety of novel chemotherapeutic agents have been evaluated in AML including topoisomerase I inhibitors such as topotecan and campothecin, platinum containing agents (carboplatin) and new anti-metabolites including gemcitabine, troxcitabine and clofarabine (Smith M, et al., Critical Reviews in Oncology/Hematology. 2004; 50(3): 197-222). All of these agents have activity against leukaemic blasts but their use remains investigational. MDR-1 blockade using cyclosporine A or PSC 833 is not of proven benefit and may either increase toxicity or necessitate dose reduction and hence reduce overall chemotherapy exposure (Larson R A. et al, Leukemia 2003; 17: 488-91).
Because chemotherapy also usually kills normal cells, patients receiving chemotherapy often experience side effects such as, for example, nausea, fatigue, and higher risk of infection.
Therefore, there is a clear and unmet need for effective therapeutics for treatment of haematologic malignancies, including leukaemias, with reduced toxicity.